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February 1, 2007

Acute Pulmonary Embolism

Christopher Kabrhel, M.D.
Acute pulmonary embolism (PE) is a common and potentially deadly disease, which occur when arteries become blocked, PE is part of a family of diseases that occur when veins become blocked.

Dr. Kabrhel is Instructor of Surgery, Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA. Within the past 12 months, Dr. Kabrhel reports no commercial conflicts of interest.

Introduction
Acute pulmonary embolism (PE) is a common and potentially deadly disease. Like other cardiovascular diseases, for example heart attacks or strokes, PE involves the blockage of a blood vessel. However, unlike heart attacks or strokes, which occur when arteries become blocked, PE is part of a family of diseases that occur when veins become blocked. This family of diagnoses is called venous thromboembolism, or VTE.

The process that ends in a PE usually begins when a blood clot forms in one of the large veins of the legs. This is called a deep vein thrombosis, or DVT. If this blood clot becomes dislodged it can flow (the medical term is 'embolize') back from the leg, through the heart and become wedged in one of the blood vessels (pulmonary arteries) of the lungs. This is called a PE. While the vast majority of PEs are caused by blood clots, it is worth noting that in rare cases they are caused by tumors, air, fat or amniotic fluid.

PE is an important public health problem. It is estimated that there are between 500,000 and 600,000 cases of acute PE in the U.S. each year, leading to an estimated 50,000 to 200,000 deaths. This makes PE the third most common cause of cardiovascular death in the U.S., behind only heart attack and stroke.

PE can strike anyone but people at particularly high risk include older individuals, cancer patients, people who recently had surgery or trauma, pregnant women, women on oral contraceptives or estrogen containing hormone replacement therapy, and people with certain genetic or inflammatory disorders. The most obvious symptoms of PE are shortness of breath and chest pain. Unfortunately, these symptoms can be subtle and overlap with many other diagnoses. As a result, physicians will typically test 10-20 patients for every case of PE they diagnose. Fortunately, in the past few years the tests available for diagnosing PE have improved dramatically, as have the treatments.

PE [is] the third most common cause of cardiovascular death in the U.S., behind only heart attack and stroke.

This article will discuss factors that put people at risk for developing PE, the tests used for diagnosis and common treatments.

Risk Assessment
The first step in the evaluation of possible PE is to assess an individual's risk. The major risk factors are increasing age, a history of prior PE or deep vein thrombosis (DVT), active cancer, prolonged immobilization of an extremity, recent surgery (especially orthopedic surgery), recent trauma to an extremity, pregnancy and oral contraceptive use (especially in smokers). There are also genetic, or inherited, risk factors that make a person more prone to developing blood clots. The inherited risk factor that causes the greatest risk is called Factor V Leiden, which increases a person's lifetime risk of thromboembolism by between 7 and 50 times. Other genetic risk factors such as Protein C or S deficiency triple the lifetime risk.

"Pretest Probability"
When a physician thinks a patient might have a PE, he/she will weigh the patient's risk factors along with their symptoms, vital signs and physical examination. The physician will then determine the likelihood that the patient has a PE, before any testing is done. Physicians call this determination the patient's "pretest probability." Pretest probability is an important concept. Physicians use it to decide which tests should be done and how they should interpret test results. This means that patients with different pretest probability sometimes need different, more or fewer tests to determine whether they have a PE.

Physicians usually use their experience to determine a patient's pretest probability of PE11, though researchers have developed decision aids to help with this process. The most well known of these is called the "Wells Score." It includes seven items related to risk factors, physical examination findings and the physician's clinical impression. Studies have shown that the Wells Score is accurate at predicting PE. A score of less than 2 means a pretest probability of PE of about 4%; a score less than 4 means a pretest probability of PE of about 5-8%; and a score more than 6 means a pretest probability of PE of about 33-60%.

Testing
There are several types of tests that a doctor can order to diagnose or exclude (rule-out) PE. Some are blood tests but most require some kind of radiological imaging.

D-dimer
In the blood, there is a system for creating (called thrombogenesis) and breaking down (called thrombolysis) clots. This system allows your body to heal cuts and minor injuries to blood vessels, and it is usually in perfect balance. Sometimes however, the system becomes out of balance, and a blood clot forms. When this happens, your body immediately begins the process of breaking that clot down. The proteins that form clots are broken down into smaller pieces — called D-dimers. Elevated levels of D-dimer in the bloodstream can therefore tell physicians there are blood clots present. Evidence shows that nearly all patients with PE have an elevated D-dimer level. In other words, there are not many "false negatives," so if you have a normal D-dimer level, you probably don't have a PE.

Because there are so many false positives, a positive D-dimer test cannot be used to diagnose PE. If a patient has a positive D-dimer level, they need further testing.

Unfortunately, no test is perfect. While most patients with PE have an elevated D-dimer, many patients without PE also have an elevated D-dimer. In other words, there are lots of "false positives." This is because D-dimers are formed as a normal part of the body's system of creating and breaking down clots. It's also because many other processes can lead to the formation of clots — which may or may not be in the bloodstream. Examples include pregnancy, cancer, autoimmune diseases like Lupus, surgery, trauma, and even advancing age. You may have noticed that many of these items are also on the list of risk factors for PE. This overlap makes knowing when to use D-dimer tests very challenging for physicians. Because there are so many false positives, a positive D-dimer test cannot be used to diagnose PE. If a patient has a positive D-dimer level, they need further testing.

Imaging Tests
There are several types of imaging tests available for patients with possible PE. The most commonly used test is a CT Scan (or CAT Scan) of the chest and the pulmonary arteries. Physicians sometimes refer to this test as a CTPA (for Computed Tomography Pulmonary Angiography) or sometimes just a PE-CT. It is done by injecting a contrast material (with iodine) into a vein in the arm and taking a picture of the arteries in the lungs as the contrast material flows through.

Studies have shown that these PE-CT scans are safe and detect about 90% of all PE.Unfortunately again, no test is perfect and there are still false negatives and false positives associated with PE-CT. If a physician is not convinced by the results of a PE-CT (for example, if the patient's pretest probability of PE is high but the PE-CT does not show a PE), he/she may order additional tests.

Other imaging tests are available to diagnose PE, though they are used less commonly than PE-CT. Ventilation/perfusion scanning is a test performed by the hospital's nuclear medicine department. It involves breathing in one radioisotope, injecting another radioisotope and comparing how the two fill the lungs. Areas of lung that fill with isotope when breathed but not when injected through the bloodstream must have something blocking the blood flow — i.e., a clot. This test was very common before PE-CT was developed, but it is limited by the fact that many patients have non-diagnostic (i.e., not positive or negative) tests. Catheter Pulmonary Angiography has long been the gold standard test, as it shows very detailed images of the pulmonary arteries. However, it involves threading a catheter through a blood vessel in the groin up into the lungs, so it is invasive, technically difficult, and carries a risk of complications. Ultrasound can be used to identify blood clots in the leg veins, but this test is only helpful when positive because many patients with PE no longer have blood clots in the leg veins (the clots have traveled to the lungs).

Treatment
Once diagnosed, patients with PE must be treated promptly. If left untreated, as many as 25% of people with acute PE will die of the disease. Fortunately, with proper treatment the mortality of PE drops to 5-10%. The mainstay of treatment of PE is anticoagulation — i.e., blood thinners. These medicines tilt the balance in the blood away from creating clots and towards breaking down clots.

For decades, the standard treatment for acute PE has been unfractionated heparin. Heparin is a naturally occurring blood thinner that is given through a continuous IV drip. More recently however, low-molecular-weight, or "fractionated" heparin has emerged as a safe and effective alternative to unfractionated heparin. Low-molecular-weight heparin can be given as a subcutaneous (just below the skin) injection once or twice a day, rather than a continuous drip. The level of anticoagulation with low-molecular-weight heparin is also more reliable, and recent studies suggest similar or lower rates of recurrent PE and major bleeding when patients are treated with low-molecular-weight heparin versus unfractionated IV heparin.

Some people react badly to heparin products but there are alternative anticoagulants. They include synthetic heparin analogues (e.g., fondaparinux) and direct thrombin inhibitors (e.g., hirudin, bivalirudin and argatroban).

Eventually, most patients with PE will be converted from heparin to a blood thinner that can be taken as a pill. The most commonly prescribed oral anticoagulant in the U.S. is warfarin. Warfarin takes several days to work, so it can't be used in the treatment of acute PE, but it is a very effective blood thinner overall. The level of anticoagulation can vary from person to person, and from day to day, so patients on warfarin require frequent monitoring of the "thinness" of their blood. Also, some patients with PE, such as those with cancer, do better on heparin than on warfarin, so long-term treatment with a low-molecular-weight heparin may be appropriate.

For those with very large PE resulting in unstable vital signs (blood pressure, heart rate), anticoagulation therapy may not be enough. These patients may need strong drugs that actively dissolve the blood clot (called thrombolytics). The most commonly used thrombolytic medicine is called tissue plasminogen activator (tPA). While tPA is a very potent medicine for dissolving PE, it carries a 2-5% risk of major bleeding, so it should be reserved for the most severe cases of PE.

Summary
PE is a common and potentially fatal disease that affects several hundred thousand Americans every year. Timely diagnosis and treatment is of utmost importance, though PE symptoms are often nonspecific and the diagnosis can be difficult to make. Evaluating a patient for PE requires physicians to combine a patient's pretest probability with the results of diagnostic tests. The most commonly used tests for PE are the D-dimer blood test and CT scanning of the pulmonary arteries. While each of these tests has limitations, they are generally very accurate and represent great advances over previous diagnostic options. Once a patient is diagnosed with PE, treatment usually consists of anticoagulation with heparin, and eventually warfarin, though thrombolysis may be needed to treat a large PE.

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